Chlamydia trachomatis serovars A-L3 are the causative agents of hyperendemic blinding trachoma, a largely neglected disease of the developing world, and sexually transmitted infections (STI) that are epidemic worldwide. Chlamydial STI are risk factors for HIV and a cervical cancer co-factor. Control of these important human diseases is the long term goal of this project. Towards this end our goal is to develop a safe and efficacious live attenuated vaccine to prevent these diseases. The obligate intracellular life style, complex developmental biology, and antigenic structure of chlamydiae have severally hindered progress in vaccine development. A live-attenuated vaccine (LAV) will be beneficial in circumventing these difficulties. We have made a plasmidless trachoma strain and found it to be highly attenuated for the monkey eye. Ocular infection with the LAV is immunogenic and induces solid protective immunity to challenge with virulent chlamydiae. Interestingly, LAV immunity was shown to be superior to natural infection mediated immunity. Ongoing studies are aimed at understanding differences in vaccine versus natural immunity by performing transcriptional analysis of ocular tissues. These findings should guide further vaccine studies that are capable of preferentially targeting protective versus pathology immunity.